Mesothelin-induced lysosomal biogenesis sustains neutrophil longevity to drive brain metastasis

Tumor-associated neutrophil (TAN) enrichment is a defining feature and driving force of brain metastases (BrMs), a leading cause of death in solid tumors. Yet, the mechanisms governing TAN enrichment in BrM remains undefined. Herein, we demonstrate that BrM cell-derived shed soluble mesothelin (sMSLN) critically prolongs neutrophil survival to facilitate tumor cell colonization and outgrowth in the brain. Specifically, sMSLN binds to toll-like receptor 4 (TLR4) on neutrophil to activate the JAK2-STAT3 pathway. This activation promotes lysosomal biogenesis and function, reducing cellular reactive oxygen species (ROS) and inhibiting neutrophil apoptosis. Neutrophil depletion or TLR4-STAT3 blockade abrogates sMSLN-induced BrM progression. Targeting MSLN with Anetumab effectively reduces TAN enrichment, and combining this with TLR4 inhibition synergistically suppresses lung cancer BrM. Our findings establish a critical role for tumor cell-derived sMSLN in sustaining neutrophil longevity and driving BrM, highlighting the sMSLN-TLR4 axis as a promising therapeutic target for brain metastatic tumors.